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Despite the ongoing advent of more effective immunomodulators and proteasome inhibitors, multiple myeloma (MM) remains incurable and no effective therapy is available for advanced aggressive disease. Although allogeneic (Allo) hematopoietic cell transplantation (HCT) has a curative potential, the outcomes remain poor because of high treatment-related mortality (TRM), mostly due to regimen-related toxicities and graft-versus-host disease (GVHD) in case of myeloablative conditionings, high relapse rate in case of reduced-intensity or nonmyeloablative regimens, and possibly other unknown MM-specific issues. In an attempt to improve TRM, without compromising conditioning intensity, we prospectively explored the feasibility and efficacy of a myeloablative but reduced-toxicity conditioning regimen, consisting of fludarabine and busulfan (FluBu4; fludarabine 40 mg/m 2 /day and busulfan 3.2 mg/kg/day i.v. × 4 days) in 22 patients with high-risk or advanced refractory MM. The majority (14 of 22, 64%) had prior autologous HCT. The median HCT-specific comorbidity index score was 3 (range, 0 to 6), with 46% having a Karnofsky performance score < 80%. Ten patients had unrelated donors, 3 of whom were 7/8 HLA–loci matched. GVHD prophylaxis was tacrolimus and methotrexate in 20 (91%). Most patients had active MM at transplantation, with a partial response in 12 of 22 (46%) and stable disease in 1 of 22 (4.5%). All 22 patients tolerated the FluBu4 conditioning well, without early toxic deaths or graft failure. Common regimen-related toxicities included mild to moderate mucositis (18 of 22, 82%) and mild transient liver function abnormality (9 of 22, 41%). There were no grade 4 toxicities but grade 3 mucositis occurred in 7 of 22 patients (32%). The cumulative incidence of severe, grades III and IV acute GVHD at day 180 was 23% (95% confidence interval [CI], 10% to 47%) and that of chronic GVHD was 68% (95% CI, 46% to 88%). The cumulative incidences of TRM at 100 days, 1 year, and 3 years were 9% (95% CI, 2% to 33%), 19% (95% CI, 7% to 44%), and 29% (95% CI, 13% to 55%), respectively. Two TRMs were due to idiopathic pneumonia syndrome and 1 was due to cirrhosis. They all had decreased pre-HCT corresponding organ function, with HCT-specific comorbidity index scores of > 3. With a median follow-up of 58.7 (range, 39 to 82) months, the cumulative incidences of relapse at 1 and 3 years were 37% (95% CI, 20% to 61%) and 50% (95% CI, 29% to 75%); those for 1-year and 3-year overall survival (OS) were 58% (95% CI, 40% to 83%) and 29% (95% CI, 15% to 57%), respectively, and those for the 1-year and 3-year progression-free survivals (PFS) were 40% (95% CI, 23% to 67%) and 15% (95% CI, 5% to 42%), respectively. In summary, the use of the myeloablative FluBu4 conditioning Allo-HCT for high-risk MM resulted in decreased TRM, compared with that of Allo-HCT using conventional myeloablative regimens; however, the relapse rate was high, including in those developing moderate-to-severe chronic GVHD. This suggested a less robust graft-versus-myeloma effect against high-risk MM, thus resulting in poor PFS and OS. Nonetheless, the FluBu4 regimen may be used as a lower-TRM platform to combine with other strategies, eg, addition of an MM-targeted agent and/or maintenance therapy with these agents, to decrease relapse or progression in patients with high-risk MM. [ABSTRACT FROM AUTHOR]

A letter to the editor on long-term safety and efficacy of cyclosporin A therapy for T-cell large granular lymphocyte leukemia is presented.

Abstract: The BCR/ABL tyrosine kinase inhibitor imatinib mesylate produces a high rate of cytogenetic responses in patients with Philadelphia (Ph)-positive chronic myeloid leukemia (CML), but secondary clonal chromosome abnormalities may develop in Ph-negative cells, and acute myeloid leukemia (AML) has been reported in patients with secondary chromosome abnormalities. We report a patient who developed AML during imatinib treatment of Ph-positive CML despite a cytogenetic response and absence of secondary chromosome abnormalities. Thus, development of AML as a rare event in CML patients with cytogenetic responses to imatinib therapy does not depend on the development of secondary cytogenetic abnormalities. [Copyright &y& Elsevier]

We sought to determine the effects of the immunosuppressants, cyclosporin A (CsA), tacrolimus and sirolimus, on drug transport by the ATP-binding cassette proteins, P-glycoprotein (Pgp; ABCB1), multidrug resistance protein-1 (MRP-1; ABCC1) and breast cancer resistance protein (BCRP; ABCG2), and the major vault protein lung resistance protein (LRP). Cellular content of mitoxantrone, a Pgp, MRP-1 and BCRP substrate, was measured by flow cytometry in cells overexpressing these proteins following incubation with and without CsA, tacrolimus or sirolimus. Interaction of BCRP with these compounds was studied by photolabeling and ATPase assays. Nuclear–cytoplasmic distribution of doxorubicin was studied by confocal microscopy in cells overexpressing LRP. CsA increased cellular drug uptake in cells overexpressing Pgp, MRP-1 or BCRP and nuclear drug uptake in cells overexpressing LRP at the clinically achievable concentration of 2.5 μM. Tacrolimus enhanced cellular drug uptake at 1 μM, but not at 0.08 μM, its clinically achievable concentration, and did not enhance nuclear drug uptake. Sirolimus enhanced cellular drug uptake in cells overexpressing Pgp, MRP-1 and BCRP with optimal effects at 2.5 μM, but was effective at its clinically achievable concentration of 0.25 μM if cells were pre-incubated for at least 30 min before drug exposure, and also enhanced nuclear drug uptake at 0.25 μM. BCRP modulation by all three immunosuppressive agents was associated with competitive binding to the drug transport sites. CsA, tacrolimus and sirolimus modulate drug transport by Pgp, MRP-1 and BCRP and CsA and sirolimus modulate drug transport by LRP at concentrations that differ from immunosuppressive concentrations and maximum tolerated concentrations. [ABSTRACT FROM AUTHOR]

Purpose: We sought to determine the effects of the immunosuppressants, cyclosporin A (CsA), tacrolimus and sirolimus, on drug transport by the ATP-binding cassette proteins, P-glycoprotein (Pgp; ABCB1), multidrug resistance protein-1 (MRP-1; ABCC1) and breast cancer resistance protein (BCRP; ABCG2), and the major vault protein lung resistance protein (LRP).Methods: Cellular content of mitoxantrone, a Pgp, MRP-1 and BCRP substrate, was measured by flow cytometry in cells overexpressing these proteins following incubation with and without CsA, tacrolimus or sirolimus. Interaction of BCRP with these compounds was studied by photolabeling and ATPase assays. Nuclear-cytoplasmic distribution of doxorubicin was studied by confocal microscopy in cells overexpressing LRP.Results: CsA increased cellular drug uptake in cells overexpressing Pgp, MRP-1 or BCRP and nuclear drug uptake in cells overexpressing LRP at the clinically achievable concentration of 2.5 microM. Tacrolimus enhanced cellular drug uptake at 1 microM, but not at 0.08 microM, its clinically achievable concentration, and did not enhance nuclear drug uptake. Sirolimus enhanced cellular drug uptake in cells overexpressing Pgp, MRP-1 and BCRP with optimal effects at 2.5 microM, but was effective at its clinically achievable concentration of 0.25 microM if cells were pre-incubated for at least 30 min before drug exposure, and also enhanced nuclear drug uptake at 0.25 microM. BCRP modulation by all three immunosuppressive agents was associated with competitive binding to the drug transport sites.Conclusions: CsA, tacrolimus and sirolimus modulate drug transport by Pgp, MRP-1 and BCRP and CsA and sirolimus modulate drug transport by LRP at concentrations that differ from immunosuppressive concentrations and maximum tolerated concentrations. [ABSTRACT FROM AUTHOR]

Abstract: A growing body of literature reports therapy-related myelodysplastic syndrome (t-MDS) and acute myeloid leukemia (t-AML) in patients treated successfully for acute promyelocytic leukemia (APL). We report a t-MDS with an isochromosome 1q as a sole abnormality, 47,XY,+1,i(1)(q10), in a 46-year-old man with APL 14 years after he was treated with cytosine arabinosine and daunorubicin. The literature on t-MDS/t-AML after APL therapy and on isochromosome 1q is reviewed. [Copyright &y& Elsevier]

AbstractBackground and Aims: Primary hepatocellular carcinoma (HCC) is common in Thailand and its prognosis is extremely poor. Hepatic resection and liver transplantation are modes of curative therapy and various therapies have been developed to treat inoperable HCC. This study was performed to determine the outcome of therapy and to identify prognostic factors for survival among Thai patients with HCC. Methods: Three hundred and sixty-eight patients with tissue-proven or serodiagnosed HCC were studied. Differences in laboratory investigations, patient survival, treatment outcomes and prognostic factors were analysed. The Kaplan–Meier method and the log-rank test were used to calculate and compare survival of patients receiving different therapies. Results: Of the 368 patients 317 were males (86.1%, M: F ratio 6.2: 1). The median age of all patients was 52 years range (2–85 years). Fifty-nine patients were specifically treated and 209 were conservatively treated. Among those tested, 70% had hepatitis B virus-related HCC. The overall median survival (range) after diagnosis and that of the treated and untreated patients were 5.6 (0–92.1), 9.0 (0–92.1) and 2.3 (0–25.9) months, respectively. More than 50% of the Okuda I patients survived beyond 30 months. The Okuda II and III patients had a median survival (range) of 5.7 (0.1–75.2) and 1.6 (0.1–25.9) months, respectively. Those patients treated by surgery, transcatheter oil chemoembolization and systemic chemotherapy had a better survival rate than did the conservatively managed patients. Surgery was found to be a better treatment than systemic chemotherapy. However, no differences between other pairs of treatment groups were identified. Subgroup analysis of the Okuda II group patients revealed the same results. Independent predictors of death were multiple lesions, advanced Okuda stage and treatment modality. Conclusion: Despite various kinds of therapy, the treatment outcomes for Thai HCC patients remain poor and largely depend on the disease extent and treatment received. Most Thai HCC patients are at an advanced stage at diagnosis. Thai patients who received disease-specific treatment other than intra-arterial chemotherapy had a better survival rate than did supportive treatment patients. [ABSTRACT FROM AUTHOR]

Introduction Relapse remains a significant challenge towards improving survival after allogeneic hematopoietic transplantation (HCT) for Acute Myeloid Leukemia (AML) not in remission or possessing poor cytogenetic/molecular features. Insights from murine pre-clinical studies demonstrate a central role for CD8+ dendritic cells in cross-presentation of leukemia associated antigens (LAA) in mediating GVL without aggravating acute Graft-versus-Host Disease (aGVHD)(Toubai, Blood 2013). We posited that enhancing LAA cross-presentation with exogenous Type I Interferon (pegIFNα) would promote GVL response and reduce rates of relapse after HCT. Methods We initiated a prospective, phase I/II, clinical trial of pegIFNα administration after myeloablative conditioning for prevention of relapse in pts with detectable AML at time of HCT (resistant to induction) or with cytogenetic/molecular features conferring high relapse risk and poor survival. Pts received up to four doses of 90mcg or 180mcg pegIFNα SubQ on d -1 and d 14, 28, 42 after PBSC or BMT. aGVHD prophy was tacrolimus + MTX or MMF. The primary endpoint was to determine the incidence of relapse in pts receiving the phase II dosage of pegIFNα. We hypothesized that 30 pts assigned to the same dose would provide 80% power to detect a difference between a promising day 180 relapse rate of 40% versus a rate of 60%. Results A total of 30 pts received study treatment at a median age of 60 years (17-72). Conditioning was myeloablative FluBu (n=9), CloBu (n=20) or FluCyTBI (n=1). At time of HCT, AML was detected in 28 pts and 2 pts enrolled for poor cytogenetic/molecular risk, complex/monosomal karyotype (n=1) and FLT3-ITD+ (n=1). There was no DLT at 90mcg (n=3) and one DLT (graft failure) after escalation to 180mcg (n=27). pegIFNα was well tolerated with ≥3 doses administered to 87% of pts. ≥Grade 3 SAEs during treatment include acute kidney injury(n=1), engraftment failure(n=1), bone pain/weakness(n=1), hypotension(n=1) and hypoxemia (n=1). 29 pts (97%) experienced primary engraftment and bone marrow exam at d 30 revealed CR in 100% of pts. Thirteen pts (43%) experienced infection. Grade II-IV aGVHD and grade III-IV aGVHD occurred in 35% (20 – 56%) and 11% (4 – 30%) by day 180. The incidence of TRM was 11% (3-30%) at day 180 and 19% (8-41%) at 1-yr. The day 180 (and 1-yr) incidence of relapse was 39% (24 – 60%) in the overall cohort and 36% (20 – 58%) in 27 pts treated at the phase II dose. At a median follow up of 19 months, the 1-yr OS was 42% (27 – 65%). Conclusion These data provide initial evidence of clinical translation for pegIFNα when administered prophylactically in an AML cohort at high risk for relapse. Type I Interferon did not significantly alter toxicity or aGVHD risk and produced relatively low rates of relapse suggesting a robust GVL response. The role of type 1 IFN in reducing clinical relapse and its underlying biological mechanisms warrants additional study. [ABSTRACT FROM AUTHOR]

The author comments on research appearing within this issue of the journal concerning the frequency of B-cell dyscraisias in patients with T-cell large granular lymphocyte (T-LGL) leukemia. The diagnostic criteria of the study "Chronic B-cell dyscrasias are an important clinical feature of T-LGL leukemia," is assessed. The hypothesis that clonal T cell expansion is stimulated by aberrant B cells in the case of T-LGL leukemia associated with B-cell dyscraisias is examined.

Acute graft-versus-host disease (GVHD) is treated with systemic corticosteroid immunosuppression. Clinical response after 1 week of therapy often guides further treatment decisions, but long-term outcomes vary widely among centers, and more accurate predictive tests are urgently needed. We analyzed clinical data and blood samples taken 1 week after systemic treatment of GVHD from 507 patients from 17 centers of the Mount Sinai Acute GVHD International Consortium (MAGIC), dividing them into a test cohort (n = 236) and 2 validation cohorts separated in time (n = 142 and n = 129). Initial response to systemic steroids correlated with response at 4 weeks, 1-year nonrelapse mortality (NRM), and overall survival (OS). A previously validated algorithm of 2 MAGIC biomarkers (ST2 and REG3a) consistently separated steroid-resistant patients into 2 groups with dramatically different NRM and OS (P < .001 for all 3 cohorts). High biomarker probability, resistance to steroids, and GVHD severity (Minnesota risk) were all significant predictors of NRM in multivariate analysis. A direct comparison of receiver operating characteristic curves showed that the area under the curve for biomarker probability (0.82) was significantly greater than that for steroid response (0.68, P = .004) and for Minnesota risk (0.72, P = .005). In conclusion, MAGIC biomarker probabilities generated after 1 week of systemic treatment of GVHD predict long-term outcomes in steroid-resistant GVHD better than clinical criteria and should prove useful in developing better treatment strategies. [ABSTRACT FROM AUTHOR]

Patients with hematologic malignancies not in remission before allogeneic hematopoietic stem cell transplantation (HSCT) have a poor prognosis. To improve the antitumor activity of conditioning, we combined clofarabine with myeloablative doses of busulfan in a phase 1/2 study in nonremission hematologic malignancies. Forty-six patients were enrolled, including 31 patients with nonremission acute myelogenous leukemia (AML). Patients had a median age of 53 years, with a median comorbidity index of 3. Donors were unrelated, HLA mismatched, or both in 59% of patients. Common grade III to IV nonhematologic toxicities included transient transaminitis (50%), mucositis (24%), hand-foot syndrome (13%), transient hypoxia (13%), nausea/vomiting (9%), and diarrhea (9%). All patients engrafted. Complete remission was achieved in 80% of all patients by day +30 and in 100% of AML patients without prior hematopoietic stem cell transplantation. Two-year nonrelapse mortality for all patients was 31%, and overall survival was 28%. In AML, the overall survival was 48% at 1 year and 35% at 2 years. These data suggest that clofarabine combined with myeloablative doses of busulfan is well tolerated, secures engraftment, and possesses significant antitumor activity, particularly in nonremission AML. [ABSTRACT FROM AUTHOR]

Objectives: Acute graft versus host disease (aGVHD) is a common complication of allogeneic hematopoietic cell transplant (HCT) and is associated with morbidity and mortality. Identifying those at risk for developing aGVHD is crucial for early intervention. The current study assessed whether scores on a brief cognitive screening measure could identify those that develop aGVHD by 100 days post-HCT. Methods: Participants were 37 patients undergoing allogeneic HCT, assessed prior to transplant, and at 30- and 100-days post-HCT. Of those completing all evaluations, patients were divided into those who did (n = 14) and did not (n = 16) develop aGVHD by day 100 post-HCT. At 100 days post-transplant, groups did not differ on relevant demographic factors, disease, conditioning regimen, relatedness of donor, stem cell source, steroid use, total body irradiation use, human leukocyte antigens (HLA) match, or frequency of infection. Results: At 100 days post-HCT, those with aGVHD performed significantly worse on a working memory measure than those without aGvHD. The presence of aGVHD at day 100 increased significantly with every one standard deviation decrease in working memory from baseline to 30 days post-HCT (odds ratio = 3.08; 95% CI: 1.00–9.36). These findings were observed despite a small sample size and statistically controlling for multiple analyses. Conclusions: While this study is exploratory in nature, and has a small sample size, findings suggest that early detection of working memory declines could coincide with, or signal the development of, aGVHD. Potential etiologies are discussed. Implementing early cognitive screening within the first 30 days post-HCT may be useful in identifying patients at risk for aGVHD. [ABSTRACT FROM AUTHOR]

• Post-transplantation pembrolizumab therapy with or without lenalidomide was feasible for myeloma. • The study was terminated early after failing to meet its interim analysis endpoint. • This resulted in a conversion from non-complete remission (CR) to 31% CR at day 180 post-transplantation. • This treatment is associated with a very promising 75% bone marrow flow cytometry-based minimal residual disease-negative rate. The programmed death-1 (PD-1) axis can suppress immune surveillance against multiple myeloma (MM). We tested the safety and efficacy of pembrolizumab, an anti-PD-1 antibody, in MM after autologous hematopoietic cell transplantation (AHCT). We enrolled patients with MM who did not achieve a complete response (CR) to induction therapy. The study intervention involved a total of 9 doses of i.v. pembrolizumab, with 1 dose given every 21 days starting on day +14 post-AHCT. The primary endpoint was the rate of CR at end of treatment (EOT) in patients receiving ≥2 pembrolizumab doses. Thirty-two patients were enrolled, but 3 withdrew consent before receiving the first dose. The study was terminated early after failing to meet its interim analysis endpoint to detect a 20% difference in EOT CR rate conversion. The median patient age was 59 years. All but 1 patient received triplet induction for a median of 4 cycles (range, 2 to 7 cycles), with 69% partial response (PR) and 31% very good PR (VGPR). No grade 4/5 toxicities or graft failures occurred. Among 26 evaluable patients, 23 had an EOT evaluation, and 7 of these 23 (31%) achieved CR. Two patients had EOT serologic CR but no bone marrow confirmation (CRu), and 1 patient had no EOT evaluation. Bone marrow was minimal residual disease-negative by flow cytometry in 12 of 16 patients (75%) at day +180. With a median follow-up of 23.7 months (range, 15.1 to 33.5 months), no patient achieving EOT CR/CRu had relapsed, whereas 3 patients progressed before EOT and 1 patient progressed at 8 months after EOT VGPR. The estimated 2-year progression-free rate was 83% (95% confidence interval, 68% to 100%). Our data show that early post-AHCT pembrolizumab with lenalidomide maintenance is feasible; however, the efficacy is uncertain and requires further study. This trial was registered at C l inical T rials.gov (NCT02331368). Image, graphical abstract [ABSTRACT FROM AUTHOR]

• The novel endpoint of graft-versus-host disease (GVHD)-free, relapse-free survival (GRFS) is achieved in a minority of allogeneic hematopoietic cell transplantation HCT recipients but is found to be highly prognostic for long term survival with major differences in the contribution of individual components. • Using statistical simulations, a modified form of GRFS (excluding death and chronic GVHD) that focuses on early severe events (grade III-IV acute GVHD and relapse) may serve as a useful surrogate endpoint in GVHD prevention studies given its strong associations with long-term overall survival. • Refinement of composite endpoints will necessarily occur depend on a priori assumptions of the study population as well as the intervention. The overall composite of graft-versus-host disease (GVHD)-free, relapse-free survival (GRFS), defined as survival free of grade III-IV acute GVHD (aGVHD), chronic GVHD (cGVHD) requiring systemic immunosuppressive therapy (IST), or relapse, has emerged as a useful composite in clinical trials and to capture clinically meaningful events that impact quantity and quality of survival after allogeneic hematopoietic cell transplantation (HCT). We reviewed 565 consecutive patients aged ≥18 years undergoing HCT for hematologic malignancy to analyze how baseline incidence, specifics of clinical definitions, and proposed reductions in any one individual event may dynamically alter the overall performance of the composite To determine the relative impact of each GRFS event (excluding death), we accounted for competing risks using Fine and Gray methods, and correlated each event with overall survival (OS) using Kaplan-Meier methods. The consequences of modulating individual or composite endpoints on OS, such as hypothesized reductions of events of an HCT interventional trial, were examined using Monte Carlo simulations. The median age of the cohort was 54 years (range, 18 to 73 years). The majority of patients received HLA-matched unrelated donor HCT (53%), consisting of peripheral blood stem cell grafts (90%) after myeloablative conditioning (68%). Relapse conferred the greatest risk for death (hazard ratio [HR], 7.89; 95% confidence interval [CI], 5.83 to 10.69), followed by grade III-IV aGVHD (HR, 6.16; 95% CI, 4.42 to 8.56) and cGVHD requiring IST (HR, 1.69; 95% CI, 1.16 to 2.46). The overall GRFS composite correlated with an HR of 4.81 (95% CI, 3.61 to 6.41), which was lower compared with either relapse or grade III-IV aGVHD. Statistical simulations found that modulating the combined risk of both relapse and grade III-IV aGVHD predicted the greatest change in 5-year OS. These simulations suggest that GRFS as currently defined may be less optimal for correlating with OS, and further refinement of composite endpoints is needed. Nonetheless, composite endpoints may be particularly helpful in mitigating potential difficulties in interpretation when competing risks are present, most commonly seen in HCT studies. [ABSTRACT FROM AUTHOR]

The article focuses on allogeneic haematopoietic cell transplantation for extranodal natural killer and T-cell lymphoma and association with Epstein–Barr virus (EBV). It mentions treatment with cyclophosphamide, doxorubicin and prednisolone like therapies alone generally does not provide durable remissions and reduced-intensity (RIC) or myeloablative conditioning (MAC). It also mentions relapse remains a major cause of treatment-failure.

Corticosteroid resistance after acute graft-versus-host disease (SR-aGVHD) results in high morbidity and mortality after allogeneic hematopoietic cell transplantation. Current immunosuppressive therapies for SR-aGVHD provide marginal effectiveness because of poor response or excessive toxicity, primarily from infection. α1-Antitrypsin (AAT), a naturally abundant serine protease inhibitor, is capable of suppressing experimental GVHD by downmodulating inflammation and increasing ratios of regulatory (Treg) to effector T cells (Teffs). In this prospective multicenter clinical study, we sought to determine the safety and response rate of AAT administration in SR-aGVHD. Forty patients with a median age of 59 years received intravenous AAT twice weekly for 4 weeks as first-line treatment of SR-aGVHD. The primary end point was overall response rate (ORR), the proportion of patients with SR-aGVHD in complete (CR) or partial response by day 28 without addition of further immunosuppression. Treatment was well tolerated without drug-related adverse events. A significant increase in serum levels of AAT was observed after treatment. The ORR and CR rates by day 28 were 65% and 35%, respectively, and included responses in all aGVHD target organs. At day 60, responses were sustained in 73% of patients without intervening immunosuppression. Infectious mortality was 10% at 6 months and 2.5% within 30 days of last AAT infusion. Consistent with preclinical data, correlative samples showed an increase in ratio of activated Tregs to Teffs after AAT treatment. These data suggest that AAT is safe and may be potentially efficacious in treating SR-aGVHD. This trial was registered at www.clinicaltrials.gov as #NCT01700036. [ABSTRACT FROM AUTHOR]

The oral histone deacetylase (HDAC) inhibitor (vorinostat) is safe and results in low incidence of acute graft-versus-host disease (GVHD) after reduced-intensity conditioning, related donor hematopoietic cell transplantation (HCT). However, its safety and efficacy in preventing acute GVHD in settings of heightened clinical risk that use myeloablative conditioning, unrelated donor (URD), and methotrexate are not known. We conducted a prospective, phase 2 study in this higher-risk setting. We enrolled 37 patients to provide 80% power to detect a significant difference in grade 2 to 4 acute GVHD of 50% compared with a reduction in target to 28%. Eligibility included adults with a hematological malignancy to receive myeloablative HCT from an available 8/8-HLA matched URD. Patients received GVHD prophylaxis with tacrolimus and methotrexate. Vorinostat (100 mg twice daily) was started on day 210 and continued through day 1100 post-HCT. Median age was 56 years (range, 18-69 years), and95%had acute myelogenous leukemia or high-risk myelodysplastic syndrome. Vorinostat was safe and tolerable. The cumulative incidence of grade 2 to 4 acute GVHD at day 100 was 22%, and for grade 3 to 4 it was 8%. The cumulative incidence of chronic GVHD was 29%; relapse, nonrelapse mortality, GVHD-free relapse-free survival, and overall survival at 1 year were 19%, 16%, 47%, and 76%, respectively. Correlative analyses showed enhanced histone (H3) acetylation in peripheral blood mononuclear cells and reduced interleukin 6 (P 5 .028) and GVHD biomarkers (Reg3, P 5 .041; ST2, P 5 .002) at day 30 post-HCT in vorinostat-treated subjects compared with similarly treated patients who did not receive vorinostat. Vorinostat for GVHD prevention is an effective strategy that should be confirmed in a randomized phase 3 study. [ABSTRACT FROM AUTHOR]

Background: Race/ethnicity remains an important barrier in clinical care. The authors investigated differences in the receipt of autologous hematopoietic cell transplantation (AHCT) among patients with multiple myeloma (MM) and outcomes based on race/ethnicity in the United States.Methods: The Center for International Blood and Marrow Transplant Research database was used to identify 28,450 patients who underwent AHCT for MM from 2008 through 2014. By using data from the National Cancer Institute's Surveillance, Epidemiology, and End Results 18 registries, the incidence of MM was calculated, and a stem cell transplantation utilization rate (STUR) was derived. Post-AHCT outcomes were analyzed among patients ages 18 to 75 years who underwent melphalan-conditioned peripheral cell grafts (N = 24,102).Results: The STUR increased across all groups from 2008 to 2014. The increase was substantially lower among Hispanics (range, 8.6%-16.9%) and non-Hispanic blacks (range, 12.2%-20.5%) compared with non-Hispanic whites (range, 22.6%-37.8%). There were 18,046 non-Hispanic whites, 4123 non-Hispanic blacks, and 1933 Hispanic patients. The Hispanic group was younger (P < .001). Fewer patients older than 60 years underwent transplantation among Hispanics (39%) and non-Hispanic blacks (42%) compared with non-Hispanic whites (56%). A Karnofsky score <90% and a hematopoietic cell transplantation comorbidity index score >3 were more common in non-Hispanic blacks compared with Hispanic and non-Hispanic whites (P < .001). More Hispanics (57%) versus non-Hispanic blacks (54%) and non-Hispanic whites (52%; P < .001) had stage III disease. More Hispanics (48%) versus non-Hispanic blacks (45%) and non-Hispanic whites (44%) had a very good partial response or better before transplantation (P = .005). Race/ethnicity did not impact post-AHCT outcomes.Conclusions: Although the STUR increased, it remained low and was significantly lower among Hispanics followed by non-Hispanic blacks compared with non-Hispanic whites. Race/ethnicity did not impact transplantation outcomes. Efforts to increase the rates of transplantation for eligible patients who have MM, with an emphasis on groups that underuse transplantation, are warranted. Cancer 2017;123:3141-9. © 2017 American Cancer Society. [ABSTRACT FROM AUTHOR]

The occurrence of infections after allogeneic hematopoietic stem cell transplantation (HCT) is nearly universal. However, the relationship between infections and graft-versus-host disease (GVHD) is complex and attribution of infectious-related mortality is highly inconsistent, making comparison of infectious complication rates across allogeneic HCT clinical studies difficult. We categorized infectious complications from diagnosis or 1 year before HCT (whichever occurred later) through 2 years after HCT according to timing, frequency, causative organism, severity, and contribution to mortality for 431 consecutive patients who underwent allogeneic HCT from 2008 to 2011. We then assessed the contribution of risk factors, such as the frequency of pre-HCT infections and post-HCT GVHD, on post-HCT infection frequency and severity. We found that each pre-HCT bacterial infection/year leads to an additional 2.15 post-HCT bacterial infection/year ( P  = .004). Pre-HCT viral and fungal infections were not predictors for post-HCT infections. Acute GVHD (aGVHD) significantly increased the risk of developing life-threatening (hazard ratio [HR], 1.97; 95% confidence interval [CI], 1.33 to 2.90) and fatal (HR, 2.8; 95% CI, 1.10 to 7.08) infections. Furthermore, patients who develop aGVHD experienced ~60% more infections than patients who never develop aGVHD. Quantification of infection frequency and severity for patients with and without GVHD may facilitate comparison of infectious outcomes across allogeneic HCT trials. [ABSTRACT FROM AUTHOR]

Reduced-intensity conditioning (RIC) regimens minimize early toxicity after allogeneic hematopoietic cell transplantation (HCT) by placing greater reliance on establishing a graft-versus-leukemia effect (GVL). Because graft-versus-host disease (GVHD) and GVL are tightly linked, inhibition of T cell populations that cause GVHD may lead to an unintended increased risk of relapse in the RIC setting. Although not completely understood, etanercept and extracorporeal photopheresis (ECP) are thought to ameliorate GVHD without direct T cell inhibition. We hypothesized that adding these 2 agents to a standard GVHD prophylaxis regimen of tacrolimus and mycophenolate mofetil (MMF) would improve survival by reducing GVHD-related mortality without increasing relapse rates. Therefore, we conducted a prospective phase II clinical trial that incorporated tacrolimus, MMF, etanercept, and ECP as GVHD prophylaxis in 48 patients undergoing RIC unrelated donor transplantation. The preferred RIC was fludarabine 160 mg/m 2 + busulfan 6.4 mg/kg to 12.8 mg/kg ± total body irradiation 200 cGy. Etanercept .4 mg/kg (maximum dose, 25 mg) was given subcutaneously twice weekly for 8 weeks after HCT and ECP was given for 12 treatments, starting weekly on day 28 weekly and tapering off by day 180. The median age of the study patients was 60 (range, 18 to 71) years. Donors were 7/8 (n = 14, 29%) or 8/8 (n = 34, 71%) HLA matched. All patients engrafted neutrophils at a median of 12 days. The cumulative incidence of grades II to IV acute GVHD at day 100 was 46%, but it was typically sensitive to initial steroid treatment (84% day 56 complete response/partial response rate). Overall survival at 1 year in this older, frequently mismatched unrelated donor setting was excellent (73%) because of low rates of nonrelapse mortality (21%) and relapse (19%). However, this strategy was not effective at preventing a high incidence of chronic GVHD and late deaths led to a drop in 2-year survival, declining to 56%, reflecting a high incidence of chronic GVHD. [ABSTRACT FROM AUTHOR]

The optimal intensity of conditioning for allogeneic hematopoietic stem cell transplantation (HCT) in acute myeloid leukemia (AML) remains undefined. Traditionally, myeloablative conditioning regimens improve disease control, but at the risk of greater nonrelapse mortality. Because fludarabine with myeloablative doses of intravenous busulfan using pharmacokinetic monitoring has excellent tolerability, we reasoned that this regimen would limit relapse without substantially elevating toxicity when compared to reduced intensity conditioning. We retrospectively analyzed 148 consecutive AML patients in remission receiving T cell replete HCT conditioned with fludarabine and intravenous busulfan at doses defined as reduced (6.4 mg/kg; FluBu2, n = 63) or myeloablative (12.8 mg/kg; FluBu4, n = 85). Early and late nonrelapse mortality (NRM) was similar among FluBu4 and FluBu2 recipients, respectively (day + 100: 4 vs 0 %; 5 years: 19 vs 22 %; p = 0.54). NRM did not differ between FluBu4 and FluBu2 in patients >50 years of age (24 vs 22 %, p = 0.75). Relapse was lower in recipients of FluBu4 (5 years: 30 vs 49 %; p = 0.04), especially in patients with poor risk cytogenetics (22 vs 59 %; p = 0.02) and those >50 years of age (28 vs 51 %; p = 0.02). Overall survival favored FluBu4 recipients at 5 years (53 vs 34 %, p = 0.02), a finding confirmed in multivariate analysis (HR: 0.57; 95 % CI: 0.34-0.95; p = 0.03). These data suggest that myeloablative FluBu4 may provide equivalent NRM, reduced relapse, and improved survival compared to FluBu2, emphasizing the importance of busulfan dose in conditioning for AML. [ABSTRACT FROM AUTHOR]

Bronchiolitis obliterans syndrome (BOS) is a significant post-transplant complication with low survival. BOS stage 0p (BOS 0p) is a parameter detected on pulmonary function tests (PFTs) after lung transplantation to identify patients at risk to develop BOS. We performed a retrospective study on 442 patients who underwent allogeneic stem cell transplant from 2007 to 2011 to evaluate whether development of BOS 0p is a risk factor in this population for BOS. Patients who met criteria for BOS 0p were significantly more likely to develop BOS (hazard ratio [HR], 3.22; P < .001). BOS 0p was significantly associated with a history of lung disease pretransplant (HR, 2.48; P = .001) and chronic graft-versus-host disease (GVHD) outside the lung post-transplant (HR, 23; P < .001). Finally, BOS 0p criteria were adequately sensitive in predicting BOS (85%), with a high negative predictive value (98%). Our findings suggest a routine PFT screening strategy with the intent of detecting BOS 0p, especially among patients with prior lung disease and who developed chronic GVHD, could suitably identify an at-risk population for the development of BOS. [ABSTRACT FROM AUTHOR]

Objectives: To describe a rare case of subcutaneous panniculitis-like T-cell lymphoma (SPTCL) with morphologic and immunophenotypic evidence of bone marrow involvement. Methods: Biopsy specimens of skin and subcutis and bone marrow were examined using H&E-stained sections. Immunohistochemical studies for CD2, CD3, CD4, CD5, CD7, CD8, CD20, CD30, CD56, and granzyme B were reviewed. In addition, T-cell receptor gene rearrangement studies were performed. Results: A bone marrow core biopsy demonstrated several lymphohistiocytic aggregates containing atypical, cytotoxic T cells that rimmed adipocytes and were associated with karyorrhexis. These T cells were morphologically and immunophenotypically identical to a concurrent SPTCL, expressing CD2, CD3, CD7, CD8, and granzyme B but with diminished CD5 expression. Conclusions: SPTCL may rarely involve the bone marrow. Bone marrow infiltrates show a similar morphologic and immunophenotypic appearance to those in the subcutaneous fibroadipose tissue, including rimming of adipocytes by neoplastic lymphocytes. [ABSTRACT FROM AUTHOR]

Clinical diagnosis of grade 1 acute graft-versus-host disease (GVHD) marks the beginning of a potentially progressive and fatal course of GVHD after hematopoietic stem cell transplantation (HSCT). However, interventional studies to treat early GVHD are lacking. We conducted a single-arm prospective phase II trial to test the hypothesis that treatment of newly diagnosed grade 1 acute GVHD with etanercept and topical corticosteroids would reduce progression to grade 2 to 4 within 28 days. Study patients (n = 34) had a median age of 51 years (range, 10 to 67 years) and had undergone unrelated (n = 22) or related (n = 12) donor HSCT. Study patients were treated with etanercept (.4 mg/kg, maximum 25 mg/dose) twice weekly for 4 to 8 weeks. Ten of 34 patients (29%) progressed to grade 2 to 4 acute GVHD within 28 days. The cumulative incidence of grade 2 to 4 and grade 3 to 4 acute GVHD at 1 year was 41% and 3%, respectively. Nonrelapse mortality was 19% and overall survival was 63% at 2 years. Among a contemporaneous control cohort of patients who were diagnosed with grade 1 acute GVHD and treated with topical corticosteroids but not etanercept during the study period, 12 of 28 patients (43%) progressed to grade 2 to 4 GVHD within 28 days, with a 1-year incidence of grade 2 to 4 GVHD and grade 3 to 4 GVHD of 61% (41% versus 61%, P = .08) and 18% (3% versus 18%, P = .05), respectively. Patients treated with etanercept also experienced less increase in GVHD plasma biomarkers suppression of tumorigenicity 2 (P = .06) and regenerating islet-derived 3-alpha (P = .01) 28 days after grade 1 acute GVHD diagnosis compared with contemporaneous control patients. This study was terminated early because of poor accrual. Future prospective studies are needed to identify patients with grade 1 acute GVHD at risk of swift progression to more severe GVHD and to establish consensus for the treatment of grade 1 acute GVHD. This trial is registered with ClinicalTrials.gov, number NCT00726375. [ABSTRACT FROM AUTHOR]

Summary: Background: Acute graft-versus-host disease (GVHD) remains a barrier to more widespread application of allogeneic haemopoietic stem-cell transplantation. Vorinostat is an inhibitor of histone deacetylases and was shown to attenuate GVHD in preclinical models. We aimed to study the safety and activity of vorinostat, in combination with standard immunoprophylaxis, for prevention of GVHD in patients undergoing related-donor reduced-intensity conditioning haemopoietic stem-cell transplantation. Methods: Between March 31, 2009, and Feb 8, 2013, we did a prospective, single-arm, phase 1/2 study at two centres in the USA. We recruited adults (aged ≥18 years) with high-risk haematological malignant diseases who were candidates for reduced-intensity conditioning haemopoietic stem-cell transplantation and had an available 8/8 or 7/8 HLA-matched related donor. All patients received a conditioning regimen of fludarabine (40 mg/m2 daily for 4 days) and busulfan (3·2 mg/kg daily for 2 days) and GVHD immunoprophylaxis of mycophenolate mofetil (1 g three times a day, days 0–28) and tacrolimus (0·03 mg/kg a day, titrated to a goal level of 8–12 ng/mL, starting day −3 until day 180). Vorinostat (either 100 mg or 200 mg, twice a day) was initiated 10 days before haemopoietic stem-cell transplantation until day 100. The primary endpoint was the cumulative incidence of grade 2–4 acute GVHD by day 100. This trial is registered with ClinicalTrials.gov, number NCT00810602. Findings: 50 patients were assessable for both toxic effects and response; eight additional patients were included in the analysis of toxic effects. All patients engrafted neutrophils and platelets at expected times after haemopoietic stem-cell transplantation. The cumulative incidence of grade 2–4 acute GVHD by day 100 was 22% (95% CI 13–36). The most common non-haematological adverse events included electrolyte disturbances (n=15), hyperglycaemia (11), infections (six), mucositis (four), and increased activity of liver enzymes (three). Non-symptomatic thrombocytopenia after engraftment was the most common haematological grade 3–4 adverse event (nine) but was transient and all cases resolved swiftly. Interpretation: Administration of vorinostat in combination with standard GVHD prophylaxis after related-donor reduced-intensity conditioning haemopoietic stem-cell transplantation is safe and is associated with a lower than expected incidence of severe acute GVHD. Future studies are needed to assess the effect of vorinostat for prevention of GVHD in broader settings of haemopoietic stem-cell transplantation. Funding: Merck, Leukemia and Lymphoma Society, National Institutes of Health, St Baldrick's Foundation, Michigan Institute for Clinical and Health Research. [ABSTRACT FROM AUTHOR]

Graft-versus-host disease (GVHD) causes most non-relapse mortality (NRM) after alternative donor (unrelated and mismatched related) hematopoietic cell transplant (HCT). We previously showed that increases in day +7 TNF-receptor-1 (TNFR1) ratios (posttransplantation day +7/pretransplantation baseline) after myeloablative HCT correlate with outcomes including GVHD, NRM, and survival. Therefore, we conducted a phase II trial at 2 centers, testing whether the addition of the TNF-inhibitor etanercept (25 mg twice weekly from start of conditioning to day +56) to standard GVHD prophylaxis would lower TNFR1 levels, reduce GVHD rates, and improve NRM and survival. Patients underwent myeloablative HCT from a matched unrelated donor (URD; N = 71), 1-antigen mismatched URD (N = 26), or 1-antigen mismatched related donor (N = 3) using either total body irradiation (TBI)-based conditioning (N = 29) or non-TBI-based conditioning (N = 71). Compared to historical controls, the increase in posttransplantation day +7 TNFR1 ratios was not altered in patients who received TBI-based conditioning, but was 40% lower in patients receiving non-TBI-based conditioning. The latter group experienced relatively low rates of severe grade 3 to 4 GVHD (14%), 1-year NRM (16%), and high 1-year survival (69%). These findings suggest that (1) the effectiveness of TNF-inhibition with etanercept may depend on the conditioning regimen, and (2) attenuating the expected rise in TNFR1 levels early posttransplantation correlates with good outcomes. [Copyright &y& Elsevier]

Allogeneic HCT is the only established curative therapy for high risk hematologic malignancies. The major challenges are leukemia relapse and high grade GVHD. We have developed the CD24Fc fusion protein to selectively inhibit danger-associated molecular pattern (DAMP)-induced inflammation and discovered that it effectively prevents GVHD without affecting the desirable GVL effect in preclinical models. With the support of SBIR awards from the NCI, we have completed a phase II randomized, double blind, multi-center, dose escalation trial comprised of 3 dosing cohorts of 8 patients (3:1 CD24Fc vs. placebo), with a total enrollment of 24 subjects. Notably, clinical data from this trial demonstrate that CD24Fc reduces the incidence of severe GVHD, resulting in statistically significant increases of acute 180-day GVHD-free survival (aGFS). A Phase II expansion cohort to enroll an additional 20 subject is ongoing (NCT02663622). Here we propose a phase III clinical trial with 180 patients (1:1 CD24Fc vs placebo) to test the hypothesis that CD24Fc prophylaxis can significantly improve 180 day acute GVHD-free survival (aGFS) over placebo control. A Randomized, Double-blind, Placebo-controlled, Multi-Center, Phase III Study of CD24Fc for the Prevention of Acute GVHD Following Myeloablative Allogeneic HCT (CATHY) (NCT04095858). This study will compare CD24Fc or Placebo with standard GVHD prophylaxis of tacrolimus and methotrexate in the setting of myeloablative conditioning (MAC), matched unrelated donor (MUD) allogeneic HCT in patients with AML/ALL or MDS. Patients will be randomized 1:1 to receive CD24Fc or placebo at the dose levels of 480mg, 240mg and 240mg on Days -1, +14 and +28, respectively. The primary endpoint is the rate of 180 days grade III-IV acute GVHD-free survival (aGFS). Secondary endpoints are 1 yr DFS, 1 yr OS, and D180 Gr II-IV aGFS. Other exploratory evaluations will be 1 yr chronic GVHD, 1 yr relapse, NRM at 1 year, incidence and rate of infection at 100 days, and rate of Gr III and above mucositis at 28 days. The study will enroll 180 patients, or 90 per arm, with an estimated accrual period of 24 months. The study will include one interim analysis for efficacy. Z test statistics for comparing the two arms will be compared to the critical values and results be reviewed by the independent DSMB. [ABSTRACT FROM AUTHOR]

Danger-associated molecular patterns (DAMPs) released during conditioning have been shown to amplify experimental GVHD. CD24 fusion protein (CD24Fc; OncoImmune), a glycoprotein linked to human IgG 1 Fc, binds to Siglec-10 to negatively regulate host response to DAMPs. We have reported that infusion of CD24Fc prior to HCT significantly decreased GVHD-related mortality in murine models of HCT (Toubai, Blood 2015 & Toubai, JCI Insight 2017). We hypothesized that enhancing Siglec10-CD24 interactions by administration of CD24Fc would prevent acute GVHD. A randomized, prospective, multi-site, placebo controlled phase 2a clinical trial was initiated to investigate safety of three dose levels of CD24Fc (or blinded placebo) plus standard GVHD prophylaxis with tacrolimus and methotrexate (MTX) in matched unrelated donors. T cell replete PBSC or BMT was infused. Randomization (3:1 ratio of CD24Fc:Placebo) was in 3 cohorts of 8 pts: 240mg single dose on D -1, 480mg single dose on D -1, and a 480mg, 240mg, and 240mg multiple dose regimen on D -1, 14 and 28, respectively. The primary endpoint was safety and determination of a recommended dose. Pts were followed for secondary endpoints of aGVHD, relapse and survival at D180. The trial enrolled 24 pts (CD24Fc, n=18; Placebo, n=6) with minimum follow up on one year (Table1). All planned dosages were administered without reaching an MTD. There were no infusion-related toxicities or DLTs. In placebo treated pts, there was one DLT resulting in death from pneumonia. Between groups there were no overall differences in AEs, although CD24Fc was associated with fewer days of severe (≥ Grade III) mucositis. There was no infection-related mortality related to CD24Fc treatment. The CD24Fc pts achieved neutrophil and platelet engraftment at a median of D 13 (12-23) and D 13 (9-23), respectively. PK studies demonstrated sustained drug levels through D 100 in the multi-dosing cohort. The incidence of grade II-IV GVHD was 39% (18-62%) and III-IV GVHD was 6% (95% CI 0-20%) at D 180 among CD24Fc treated pts. Grade 3 involvement of the lower-GI tract was observed in 1/18 pts, while the remainder of acute GVHD involved the upper GI tract or skin. All pts receiving treatment for GVHD experienced response. At D 180, relapse occurred in 2/18 pts, and OS was 100%. The endpoint of grade 3-4 GVHD-free survival (AGFS) was 94% at D 180 in pts receiving treatment with CD24Fc versus 50% in pts receiving placebo (HR 0.1; 90% CI 0.0-0.7). AGFS in contemporaneous case matched controls (n=68; CIBMTR) receiving myeloablative 8/8 HLA matched unrelated donor HCT with tacrolimus + MTX was 68% (95% CI: 56-78). In this translational phase 2a trial administration of CD24Fc was safe and tolerable. Additional investigations are required determine efficacy for improving AGFS after HCT. This trial represents the first attempt to prevent GVHD by inhibiting host response to DAMPs. [ABSTRACT FROM AUTHOR]

Introduction Genomic minimal residual disease (MRD) detected in complete remission using droplet digital PCR (ddPCR) is associated with inferior survival in AML patients when measured after induction chemotherapy and before and after allogeneic HSCT. However, the utility of high sensitivity genomic MRD detection in the context of allogeneic HSCT for patients with myelodysplastic syndrome (MDS) is unclear. Here we present data evaluating the association of genomic MRD with survival in HSCT recipients with MDS. Methods Peripheral blood mononuclear cells (PBMC) from 72 MDS patients sampled prior to HSCT were enriched for CD34+ cells and CD3+ cells using MACS columns. Genomic DNA extracted from CD34+ fractions underwent targeted next generation sequencing of 49 genes recurrently mutated in MDS. Variants were confirmed in the CD34+ fraction and germline polymorphisms excluded in the CD3+ fraction using Sanger resequencing. To date, mutations identified in 43 cases have been quantified with ddPCR in unfractionated PBMC genomic DNA prior to conditioning and at day 30 post-transplant with a sensitivity as low as 0.002%. Results A median of 2 mutations per case (range 1-4) was identified with NGS and subsequently measured with ddPCR. Prior to HSCT, 70% of cases had mutations with a variant allele frequency (VAF) ≥10% and had inferior OS compared to those with <10% VAF (HR 2.7 [1.2-5.7], p=0.04). At Day 30 after HSCT, 65% of patients still had detectable mutations in circulating PBMC (≥0.002% VAF) (MRDpos) and had inferior DFS (median 347d vs not reached; HR 3.6 [1.6-8.1], p<0.01) and OS (median 560d vs not reached; HR 4.0 [1.7-9.2], p<0.01) compared to patients with undetectable mutations (MRDneg). TP53 mutations remained detectable in all cases (8 of 8) along with most DNMT3A (4 of 7), RUNX1 (3 of 4), ASXL1 (3 of 5) and spliceosome gene mutations (5 of 8). The 1-year relapse rate was 35% in the MRDpos group and 5% in the MRDneg group (p=0.02). Non-relapse mortality in the MRDpos and MRDneg groups was 44% and 31%, respectively (p=0.99). In bivariate analyses, DFS and OS remained significantly inferior in MRDpos patients versus MRDneg patients when controlled for age, cytogenetics, IPSS-R at diagnosis or pre-HSCT, or presence of adverse gene mutations. In addition, MRDpos patients with mutations detected at <0.1% VAF (58% of MRDpos cases; median 0.009%, range 0.002-0.082% VAF) had equally inferior DFS and OS as MRDpos patients with mutations detected at ≥0.1% (42% of MRDpos cases; median 0.48%, range 0.12-16.1% VAF). Conclusion Ultrasensitive genomic MRD detection in PBMC of MDS patients 30 days after HSCT is feasible and is associated with increased relapse risk and inferior DFS and OS. The gene mutations of most MRDpos patients were detected at <0.1% VAF, suggesting ultrasensitive genomic MRD detection in peripheral blood identifies patients with very low level MRD at high risk for relapse and death post-HSCT. [ABSTRACT FROM AUTHOR]

INTRODUCTION The composite endpoint of GVHD-free, relapse-free survival (GRFS), defined as survival free from grade 3–4 acute GVHD (aGVHD), chronic GVHD (cGVHD) requiring systemic immunosuppressive therapy (IST), or relapse has emerged as an outcome to capture clinically meaningful events. In the present study, we validated GRFS as a useful surrogate endpoint by examining the relative importance of individual events and the GRFS composite itself on overall survival (OS) at 5-years after allogeneic HCT. METHODS We conducted an IRB-approved retrospective cohort study on 565 consecutive patients (age ≥18 years) undergoing first-time allogeneic HCT for hematologic malignancy (January 2007–March 2013). Data abstraction of GRFS events was performed through chart review of the EHR. To determine the impact of each event of the GRFS composite endpoint, we accounted for competing risks using Fine and Gray methods, and correlated each event with OS using Kaplan-Meier methods. Using statistical simulations, the relative consequences of successfully modulating individual or composite endpoints on OS were examined to further elucidate the role of GRFS in clinical trials research. RESULTS The median age of the cohort was 54 years (18–73 years), comprised predominantly of males (58%) and Caucasians (94%). The most common indication for transplant was AML (41%), followed by lymphoma (21%) and MDS/MPD (14%). Patients received HLA-matched related (47%), and matched unrelated (53%) donors, and mostly peripheral blood stem cells (90%) and myeloablative conditioning (68%). Relapse conferred the greatest risk for death (HR 7.89; 95% CI:5.83–10.69). Grade 3–4 aGVHD was associated with HR 6.16 (95%CI:4.42–8.56), while cGVHD requiring IST was associated with lower HR 1.69 (95%CI:1.16–2.46). Indeed, the GRFS composite correlated with less HR 4.81 (95% CI:3.61–6.41) compared with either relapse or grade 3–4 aGVHD events. To determine the impact of hypothetical improvements on individual events or combined events (composite) on OS, we next performed Monte Carlo simulations. Compared with individual events, modulating composite endpoints predicted the greatest change in 5-year OS (Figure 1). The greatest gain in OS was seen by proportionally reducing both grade 3–4 aGVHD and relapse (modified GRFS). Reducing chronic GVHD requiring IST proportionally with grade 3–4 aGVHD and relapse events (conventional GRFS) did not change 5-year OS. CONCLUSION These findings highlight the importance of influencing OS by targeting the major early adverse post-HCT events (i.e., grade 3–4 acute GVHD and relapse). Moreover, the simulations herein suggest that GRFS as currently defined may be less optimal for predicting OS than using early grade 3–4 aGVHD and relapse as composite endpoints. Importantly, further refinement of these endpoints will depend on the a priori defined study population as well as intervention. [ABSTRACT FROM AUTHOR]

Acute GVHD biomarkers predict long-term outcomes after GVHD diagnosis. Our group has validated the MAGIC algorithm which uses the concentrations of 2 GVHD biomarkers, ST2+REG3a, to predict lethal GVHD (defined as death from GVHD without relapse) [Hartwell 2017]. Other published biomarker combinations that predict GVHD outcomes include ST2+ REG3a+TNFR1 [Levine 2015], ST2+TIM3 [Abu Zaid 2017], ST2+TNFR1 [McDonald 2015], TIM3+TNFR1+IL6 [McDonald 2015], as well as AREG alone [Holtan 2018]. It is not clear which biomarker combination best predicts lethal GVHD because these algorithms were developed using different patient cohorts with different endpoints. To answer this question, we compared the predictive accuracy of different biomarker combinations as well as these six specific combinations in the same patient cohort. We studied 522 patients with serum samples at GVHD diagnosis who were transplanted at 19 Mount Sinai Acute GVHD International Consortium (MAGIC) centers between January 1, 2004 and April 30, 2017. Patients were divided into training (n = 253) and validation (n = 269) sets; validation patients were transplanted after November 1, 2015 and had not previously been used to generate an algorithm. Biomarkers were measured by ELISA and log-transformed values were used to predict 1-year lethal GVHD by competing risk regression. Four of the 6 biomarkers (ST2, REG3a, TNFR1, and TIM3) independently predicted lethal GVHD in the training set. We then developed algorithms that predicted lethal GVHD using all possible combinations of these 4 biomarkers as well as the published combination of TIM3+TNFR1+IL6 and AREG alone. The best algorithms of 1-4 biomarkers for predicting lethal GVHD were REG3a alone, ST2+REG3a, ST2+REG3a+TNFR1, and ST2+REG3a+TNFR1+TIM3. While ST2+REG3a was the most accurate combination based on the lowest Akaike Information Criterion (AIC), the other published biomarker combinations produced similar AICs. Therefore, we used the independent validation set to compare all six published algorithms. We generated area under the receiver operating characteristic curves (AUC) for each algorithm (FIG 1). We next determined the threshold that maximized sensitivity and specificity for each algorithm and calculated the cumulative incidence of lethal GVHD in the resulting high and low risk strata (FIG 2). Highly similar results were obtained when the cumulative incidence of non-relapse mortality was used as the endpoint. In a validation set of previously unanalyzed patients, several biomarker combinations reproducibly stratified patients with GVHD for risk of death. The best 4 algorithms, all of which included ST2, produced comparable outcomes. Adding TNFR1 to ST2+ REG3a did not improve accuracy. The ST2+REG3a algorithm best identifies patients at onset of GVHD for high risk of lethal GVHD and NRM, and thus remains a standard for biomarker-based risk prediction. [ABSTRACT FROM AUTHOR]

BACKGROUND A recent U.S. Food and Drug Administration (FDA) safety communication (Aug 2018) warned prescribers of the risk of relapse in patients receiving azithromycin as prophylaxis for bronchiolitis obliterans syndrome (BOS) following hematopoietic cell transplant (HCT). However, the FDA warning was based upon a single multicenter trial, in which patients were randomized to receive azithromycin for 2 years, starting at the time of conditioning. We now examine relapse rates in a cohort of patients treated with azithromycin for management of moderate-severe CGVHD. PATIENT POPULATION A retrospective review of our HCT database (2010-2017) identified 239 patients (median age 55 years, range 4-72) with moderate-severe CGVHD following an allogeneic HCT for a primary hematologic malignancy. NIH consensus criteria (2015) were used for CGVHD grading. Patients were divided into 2 cohorts, a) those receiving an extended course of azithromycin (≥ 14 days) for CGVHD management (cohort 1, n=86) and b) those who did not (cohort 2, n=153). Patients in cohort 2 either did not receive any azithromycin (n=122) or had received an abbreviated (<14 day) course (n=31) of azithromycin post-HCT. For cohort 1, the median time to initiation of azithromycin therapy was 15 months post-HCT (range 3-68), with a 26 month median duration of azithromycin therapy (range 1-77). All patients in cohort 1 met NIH consensus criteria for BOS. Patients in cohort 2 did not exhibit BOS, but still met NIH criteria for moderate-severe CGVHD. Hematologic conditions included acute leukemia (n=139), MDS/MPD (n=44), malignant lymphomas (n=26), chronic leukemia (n=24), and multiple myeloma (n=6). Ninety-one patients exhibited moderate and 148 patients exhibited severe CGVHD. The two cohorts were balanced for CGVHD severity, with severe CGVHD noted in 69% and 63% of patients in cohorts 1 and 2 respectively. RESULTS Decreased rates of relapse and improved survival were noted for patients treated with azithromycin for CGVHD. At 2 years, the cumulative incidence of relapse was 2% (95% CI:1-9%) for patients in cohort 1 vs 16% (95% CI: 11-23%) in cohort 2, p=0.001. Overall survival (2-year OS) in cohort 1 was 93% (95%CI: 88-99%) vs 78% (95% CI:72-85%) for cohort 2, p=0.003. Overall, 7 of 86 (8.1%) CGVHD patients treated with an extended course of azithromycin (cohort 1) have relapsed, the median time to relapse 876 days (range 379-1303) post-HCT. In comparison, 28 of 153 (18.3%) in cohort 2 have relapsed, a median 371 days (range 98-1252) post-HCT. CONCLUSION The use of azithromycin for the management of moderate to severe CGVHD was not associated with an increased risk of relapse in patients undergoing HCT for a hematologic malignancy. Azithromycin therapy for patients with CGVHD should not be contra-indicated in this patient population. [ABSTRACT FROM AUTHOR]